2XOA

Crystal Structure of the N-terminal three domains of the skeletal muscle Ryanodine Receptor (RyR1)

Summary for 2XOA

• Entry DOI: 10.2210/pdb2xoa/pdb
• Related: 2BCX
• Descriptor: RYANODINE RECEPTOR 1 (2 entities in total)
• Functional Keywords: metal transport, calcium channel, ion channel, membrane protein, malignant hyperthermia, cardiac arrhythmia
• Biological source: ORYCTOLAGUS CUNICULUS (RABBIT)
• Cellular location: Membrane; Multi-pass membrane protein (Potential): P11716
• Total number of polymer chains: 1
• Total formula weight: 61972.20

Authors

Tung, C.,Lobo, P.A.,Kimlicka, L.,Van Petegem, F. (deposition date: 2010-08-10, release date: 2010-11-10, Last modification date: 2024-05-08)

Primary citation

Tung, C.C.,Lobo, P.A.,Kimlicka, L.,Van Petegem, F.
The Amino-Terminal Disease Hotspot of Ryanodine Receptors Forms a Cytoplasmic Vestibule.
Nature, 468:585-, 2010

PubMed Abstract: Many physiological events require transient increases in cytosolic Ca(2+) concentrations. Ryanodine receptors (RyRs) are ion channels that govern the release of Ca(2+) from the endoplasmic and sarcoplasmic reticulum. Mutations in RyRs can lead to severe genetic conditions that affect both cardiac and skeletal muscle, but locating the mutated residues in the full-length channel structure has been difficult. Here we show the 2.5 Å resolution crystal structure of a region spanning three domains of RyR type 1 (RyR1), encompassing amino acid residues 1-559. The domains interact with each other through a predominantly hydrophilic interface. Docking in RyR1 electron microscopy maps unambiguously places the domains in the cytoplasmic portion of the channel, forming a 240-kDa cytoplasmic vestibule around the four-fold symmetry axis. We pinpoint the exact locations of more than 50 disease-associated mutations in full-length RyR1 and RyR2. The mutations can be classified into three groups: those that destabilize the interfaces between the three amino-terminal domains, disturb the folding of individual domains or affect one of six interfaces with other parts of the receptor. We propose a model whereby the opening of a RyR coincides with allosterically coupled motions within the N-terminal domains. This process can be affected by mutations that target various interfaces within and across subunits. The crystal structure provides a framework to understand the many disease-associated mutations in RyRs that have been studied using functional methods, and will be useful for developing new strategies to modulate RyR function in disease states.

PubMed: 21048710
DOI: 10.1038/NATURE09471

Experimental method

X-RAY DIFFRACTION (2.5 Å)